Abstract
Background
In this study, we investigated the therapeutic potential effects of G1899 Korean Red Ginseng Extract Powder(G1899) on long COVID in a general population using flow cytometry and follow-up by questionnaire.
Methods
We conducted a 12-week clinical pilot study on 220 COVID19 patients who were recently infected. The study was completed by 108 participants in the G1899 group and 108 participants in the placebo group. Participants were randomized 1:1 to the G1899 and placebo groups. We evaluated the long COVID by questionnaire including GAD-7, FSS and BFI-K at baseline and 12 weeks. To investigate the changes in the levels of CD4/CD8 T cell ratio and regulatory T cell population, multicolor flow cytometry was performed.
Results
The G1899 group showed significantly chronic fatigue symptoms relieving compared with placebo group at 12 weeks in women. The CD4/CD8 ratio increased significantly in the G1899 group, rising from 1.71 (95 % CI: 1.35–2.07) at Visit 1 to 2.31 (95 % CI: 1.83–2.78) at Visit 4 (p = 0.0029). Unlike the G1899 group, there was a significant reduction in the Treg population, from 2.02 % at Visit 1–1.22 % at Visit 4 (p = 0.0005) in the placebo group.
Conclusion
These findings suggest that G1899 has beneficial effects on the amelioration of long COVID symptoms, with more prominent effects observed in women. Although the changes in Treg population were not statistically significant in the G1899 group, the significant reduction observed in the placebo group suggests a potential protective effect of G1899 against Treg depletion.
Keywords: Korean red ginseng, Long COVID, Flow cytometry, Immune function
Graphical abstract
1. Introduction
Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), refers to persistent symptoms that continue beyond the acute phase of infection [1]. These symptoms, which can last for weeks or months after initial recovery, include fatigue, dyspnea, cognitive impairment, anxiety, and sleep disturbances, significantly impacting patients' quality of life [2]. Studies suggest that long COVID is driven by persistent inflammation, immune dysregulation, and autonomic dysfunction, contributing to prolonged health complications in affected individuals [3]. The prevalence of long COVID varies widely, with estimates indicating that a substantial proportion of COVID-19 survivors experience lingering symptoms [4]. Given its clinical burden and lack of standardized treatment, there is an urgent need for therapeutic interventions that can effectively address both the physiological and psychological manifestations of long COVID.
Korean Red Ginseng (KRG) has long been recognized for its immunomodulatory, anti-inflammatory, and antioxidative properties, making it a promising candidate for mitigating the effects of long COVID [5]. Ginsenosides, the active components of KRG, have been shown to regulate cytokine production, enhance mitochondrial function, and improve T cell homeostasis, which may be beneficial in alleviating fatigue, anxiety, and immune dysfunction observed in long COVID patients [6]. Moreover, KRG has demonstrated neuroprotective and adaptogenic effects, which could help counteract the cognitive and psychological impairments associated with long COVID [7]. Given these potential therapeutic benefits, further investigation into the clinical effects of KRG on long COVID is warranted [8].
Despite emerging evidence on the immunomodulatory and anti-inflammatory effects of KRG, limited clinical research has explored its efficacy in treating long COVID [9]. Current studies on long COVID management primarily focus on symptomatic relief and rehabilitation strategies, with few addressing underlying immune dysregulation [10]. Furthermore, while KRG has been extensively studied for its role in improving immune responses and reducing fatigue in other conditions, its effects on post-viral syndromes such as long COVID remain largely unexplored [11]. This study aims to fill this research gap by evaluating the impact of G1899 Korean Red Ginseng Extract Powder(G1899) on long COVID symptoms and immune responses through a randomized, double-blind, placebo-controlled trial, providing new insights into its potential as a therapeutic intervention for long COVID patients.
2. Materials and method
2.1. Study population
This randomized, double-blind, placebo-controlled clinical trial was conducted at Yongin Severance Hospital, South Korea, to evaluate the efficacy of G1899 in patients with COVID-19 (Clinical Research Information Service, KCT 20250116-003). Study participants were enrolled within seven days of laboratory-confirmed COVID-19 diagnosis between April 2022 and March 2023. The participants made their initial clinical assessment at the research center within one week of laboratory-confirmed COVID-19 infection to verify the diagnosis and undergo a comprehensive blood panel including glycemic parameters, hepatic function tests, renal function markers, lipid profile, and complete blood count with differential. Concurrent single-cell analysis was performed. At the second visit, conducted three week post-infection, leukocyte counts and C-reactive protein levels were measured to assess resolution of the acute inflammatory response, and repeat single-cell analysis was performed. The third assessment, conducted nine weeks post-infection, was performed via telephone. No biological specimens were collected, but a standardized questionnaire was administered to document the presence or absence of long COVID symptom. At the fourth clinical assessment, twelve weeks post-infection, the complete battery of laboratory investigations performed during the initial visit was repeated to evaluate. The study protocol was approved by the Institutional Review Board of Yongin Severance Hospital and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to study enrollment. Participants aged 35–60 years were randomized in a 1:1 ratio to receive either G1899 (2 g/day) or placebo. One hundred and eight participants in each group completed the 12-week trial. The G1899 intervention consisted of four tablets daily (total 2 g), containing ginsenosides Rb1 (8.03 mg/g), Rb2 (2.80 mg/g), Rg3 (2.50 mg/g), Rg1 (1.18 mg/g), Rc (3.29 mg/g), Rf (1.47 mg/g), Re (1.29 mg/g), and Rd (1.0 mg/g). The G1899 were manufactured by dehydrating KRG extracts (3 g per 2 g tablet). The placebo tablets, composed of corn starch and cellulose, were manufactured to be identical to the G1899 tablets in appearance, color, and taste.
2.2. Long COVID symptom analysis
At each visit, long COVID symptoms were evaluated using the Chronic Fatigue Syndrome associated with COVID-19 (CFS-COVID19) and Generalized Anxiety Disorder 7-item scale (GAD-7) questionnaires. The CFS-COVID19 questionnaire comprises eight evaluation items: myalgia, headache, odynophagia, non-restorative sleep, post-exertional malaise >24 h, painful cervical/axillary adenopathy, recent concentration/memory disorders, and polyarthralgia without inflammatory signs. These items provide valid measures of psychological, physical, cognitive, and behavioral symptoms of long COVID [12]. Chronic fatigue syndrome associated with COVID-19 is diagnosed when four or more criteria are met for more than 12 weeks. Changes in CFS-COVID19 scores were analyzed at baseline, 3 weeks, 6 weeks, and 12 weeks.
2.3. Antibody for COVID19 infection analysis
2.3.1. Detection of virus-specific antibodies
Automated ECLIA tests were performed with two types of SARS-CoV-2 antibody kits using the Cobas 8000 e801 module (Roche Diagnostics). The Elecsys Anti-SARS-CoV-2 assay (Roche Diagnostics) uses a recombinant protein representing the nucleocapsid (NC) antigen for the qualitative detection of antibodies against SARS-CoV-2. Results with <1.0 cut-off indexes (COI) were interpreted as negative for anti-NC antibodies, and those with ≥1.0 were interpreted as positive for anti-NC antibodies. The Elecsys Anti-SARSCoV-2 S assay (Roche Diagnostics) uses a recombinant protein representing the spike protein receptor-binding domain to quantitatively determine antibodies against SARSCoV-2. Results with <0.80 U/mL were interpreted as negative for anti-S-Ab, and those ≥0.80 U/mL were interpreted as positive for anti-S-Ab. All tests were performed according to the manufacturer's instructions. Anti-NC Ab was measured in the first specimen, and Anti-Sab was measured in all specimens.
2.4. Flow cytometry
Cryopreserved PBMCs were thawed and stained with fluorochrome-conjugated antibodies for 30 min at 4 °C. Following cell surface staining, cells were permeabilized and intracellular staining buffer (eBioscience) used to stain intracellular markers, such as FOXP3, IL-17 and IFN-γ. Multicolor flow cytometry was performed using an FACSFortessa (BD Biosciences) and data analyzed using FlowJo software (Treestar)
2.5. Statistical analysis
All continuous variables are presented as mean ± standard deviation, and the categorical variables are summarized as frequency (percentages) for the G1899 and placebo groups. The G1899 group was compared to the placebo group based on the primary outcome, which consisted of antibody for COVID infection and flow cytometry, as well as the secondary outcome of long COVID questionnaire. The linear mixed models were used to determine the difference of change compared to baseline between the G1899 and placebo groups. For each time point, least squares means were calculated using fitted linear mixed with 95 % confidence intervals. Significance was determined using a two-sided statistical test, with a p-value less than 0.05 being considered statistically significant. All statistical analyses were conducted using R software (version 4.4.1; R Foundation for Statistical Computing, Vienna, Austria).
3. Results
220 adults were involved in this study and were randomly assigned to either the G1899 group (n = 110) or the placebo group (n = 110) at a 1:1 ratio. One hundred eight participants in the G1899 group completed the study, with two missing measurements. In the placebo group, two participant withdrew consent, resulting in a total of 108 participants completing the study (see Fig. 1)During the 12-week clinical trial, all participants underwent a comprehensive blood panel, and single-cell analysis was conducted. Long COVID-related symptoms were systematically evaluated using a validated questionnaire. (see Fig. 2).
Fig. 1.
Flow chart for selection of study participants.
Fig. 2.
A total of 220 participants with acute COVID-19 were randomly assigned to receive G1899 (n = 110) or placebo (n = 110) for 12 weeks. The study assessed long COVID symptoms using standardized questionnaires, anti-COVID-19 spike antibody levels, and immune cell profiles via flow cytometry.
3.1. General papulation
Table 1 shows that there were no significant differences in baseline characteristics between the two groups of participants. After 12 weeks, blood pressure remained stable in both groups, with no significant differences (p > 0.05). Inflammatory markers (CRP, WBC, neutrophils, lymphocytes) showed similar reductions across groups, with no significant differences (p > 0.05). Fasting glucose and cholesterol also showed comparable trends, with no clear advantage of G1899 over placebo. No significant between-group differences were detected in the prevalence of comorbidities, including essential hypertension, T2DM, and hyperlipidemia (p > 0.05). Liver function markers (ALT, AST) remained stable, but ALT levels showed a greater reduction in the placebo group (p = 0.032)(see Table 2). Renal function markers (BUN, creatinine, eGFR) remained unchanged between groups. The change in blood cortisol levels increased by 1.21 in the G1899 group, whereas in the placebo group it increased by 2.75, showing a statistically significant higher increase compared to the G1899 group.
Table 1.
Baseline characteristics of study participants.
| Characteristic | G1899 (n = 108) | Placebo (n = 108) | p-value |
|---|---|---|---|
| Age | 43.69 ± 13.33 | 45.05 ± 12.64 | 0.445 |
| Sex | 0.141 | ||
| Male, n (%) | 28 (25.9 %) | 39 (36.1 %) | |
| Female, n (%) | 80 (74.1 %) | 69 (63.9 %) | |
| Height, cm | 168.19 ± 6.99 | 165.26 ± 8.70 | 0.340 |
| Weight, kg | 64.53 ± 11.68 | 65.46 ± 14.58 | 0.603 |
| SBP, mmHg | 126.91 ± 15.81 | 126.09 ± 16.66 | 0.713 |
| DBP, mmHg | 76.62 ± 13.43 | 76.87 ± 14.13 | 0.894 |
| Vitamin D | 21.00 ± 8.92 | 23.43 ± 10.90 | 0.074 |
| Cortisol, mcg/dL | 7.85 ± 4.97 | 8.29 ± 4.65 | 0.502 |
| CRP, mg/L | 6.73 ± 8.77 | 7.21 ± 10.63 | 0.712 |
| WBC ( × 103 L) | 6.01 ± 1.94 | 5.84 ± 2.04 | 0.510 |
| RBC ( × 106 L) | 4.54 ± 0.48 | 4.61 ± 0.41 | 0.245 |
| Hemoglobin, g/L | 13.57 ± 1.40 | 13.73 ± 1.41 | 0.387 |
| Cholesterol, mg/dL | 171.40 ± 35.32 | 166.99 ± 37.43 | 0.374 |
| Protein, g/L | 7.18 ± 0.49 | 7.15 ± 0.50 | 0.604 |
| Albumin, g/L | 4.50 ± 0.27 | 4.96 ± 4.58 | 0.305 |
| ALP (IU/L) | 65.12 ± 17.95 | 65.75 ± 18.71 | 0.801 |
| AST (IU/L) | 23.38 ± 11.03 | 21.53 ± 8.34 | 0.166 |
| ALT (IU/L) | 22.96 ± 17.08 | 20.76 ± 12.92 | 0.287 |
| Bilirubin, mg/dL | 0.41 ± 0.23 | 1.78 ± 13.72 | 0.302 |
| eGFR (mL/min/1.73 m) | 87.36 ± 5.79 | 86.21 ± 8.57 | 0.250 |
| Glucose, mg/dL | 97.20 ± 20.60 | 100.73 ± 28.99 | 0.304 |
| Hypertension, n (%) | 17 (15.6 %) | 20 (18.5 %) | 0.587 |
| T2DM, n (%) | 6 (5.5 %) | 13 (12.1 %) | 0.149 |
| Dyslipidemia, n (%) | 14 (12.8 %) | 20 (18.5 %) | 0.262 |
P-values were calculated using t-test or Pearson's chi-square test.
Abbreviations: LS, Least-squares; SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; T2DM, type 2 diabetes mellitus.
Table 2.
Changes in serum markers of G1899 and placebo before and after 12 week.
| Outcome | Visit | G1899 Group |
Placebo Group |
p-valuefor change | ||
|---|---|---|---|---|---|---|
| Lsmeans (95 % CI) | Change (95 % CI) | Lsmeans (95 % CI) | Change (95 % CI) | |||
| SBP | Visit1 | 126.39 (118.78, 134.00) | 126.61 (119.00, 134.22) | |||
| Visit2 | 133.25 (125.64, 140.86) | 6.86 (−5.96, 19.68) | 123.68 (116.07, 131.29) | −2.94 (−15.75, 9.88) | 0.204 | |
| Visit4 | 123.11 (115.50, 130.72) | −3.28 (−16.10, 9.54) | 125.11 (117.50, 132.72) | −1.50 (−14.32, 11.32) | 0.818 | |
| DBP | Visit1 | 76.78 (75.21, 78.34) | 76.72 (75.15, 78.28) | |||
| Visit2 | 73.31 (71.75, 74.88) | −3.46 (−5.93, −1.00)∗ | 73.98 (72.42, 75.55) | −2.73 (−5.20, −0.27)∗ | 0.622 | |
| Visit4 | 72.90 (71.34, 74.47) | −3.87 (−6.34, −1.40)∗ | 75.33 (73.76, 76.89) | −1.39 (−3.85, 1.08) | 0.095 | |
| CRP | Visit1 | 7.13 (6.23, 8.02) | 6.81 (5.92, 7.71) | |||
| Visit2 | 1.41 (0.52, 2.31) | −5.71 (−7.23, −4.19)∗ | 1.15 (0.25, 2.04) | −5.67 (−7.19, −4.15)∗ | 0.960 | |
| Visit4 | 1.25 (0.35, 2.15) | −5.88 (−7.40, −4.36)∗ | 1.23 (0.33, 2.12) | −5.59 (−7.11, −4.07)∗ | 0.750 | |
| WBC | Visit1 | 5.89 (5.64, 6.14) | 5.96 (5.71, 6.21) | |||
| Visit2 | 6.15 (5.90, 6.40) | 0.26 (−0.13, 0.66) | 6.18 (5.93, 6.43) | 0.22 (−0.18, 0.62) | 0.856 | |
| Visit4 | 6.09 (5.84, 6.34) | 0.20 (−0.19, 0.60) | 6.15 (5.90, 6.40) | 0.19 (−0.21, 0.58) | 0.942 | |
| Neutrophil | Visit1 | 56.38 (54.85, 57.91) | 57.17 (55.64, 58.70) | |||
| Visit2 | 55.24 (53.71, 56.77) | −1.14 (−3.73, 1.45) | 53.84 (52.31, 55.37) | −3.33 (−5.92, −0.74)∗ | 0.160 | |
| Visit4 | 54.97 (53.44, 56.50) | −1.41 (−4.00, 1.18) | 54.00 (52.47, 55.53) | −3.16 (−5.75, −0.57)∗ | 0.262 | |
| Lymphocyte | Visit1 | 32.62 (31.21, 34.04) | 32.14 (30.72, 33.55) | |||
| Visit2 | 34.20 (32.79, 35.61) | 1.58 (−0.82, 3.97) | 35.24 (33.82, 36.65) | 3.10 (0.71, 5.49)∗ | 0.290 | |
| Visit4 | 34.83 (33.42, 36.25) | 2.21 (−0.18, 4.60) | 35.78 (34.37, 37.20) | 3.65 (1.25, 6.04)∗ | 0.319 | |
| Glucose | Visit1 | 99.59 (97.24, 101.95) | 98.34 (95.99, 100.70) | |||
| Visit4 | 96.57 (94.22, 98.93) | −3.02 (−6.36, 0.32) | 97.84 (95.49, 100.20) | −0.50 (−3.84, 2.84) | 0.294 | |
| BUN | Visit1 | 12.31 (11.91, 12.71) | 12.04 (11.64, 12.44) | |||
| Visit4 | 12.45 (12.05, 12.85) | 0.14 (−0.42, 0.71) | 12.85 (12.45, 13.24) | 0.81 (0.24, 1.37)∗ | 0.101 | |
| Creatinine | Visit1 | 0.73 (0.72, 0.74) | 0.73 (0.72, 0.74) | |||
| Visit4 | 0.73 (0.72, 0.74) | −0.00 (−0.02, 0.01) | 0.74 (0.73, 0.75) | 0.01 (−0.00, 0.02) | 0.233 | |
| Cholesterol | Visit1 | 168.89 (165.38, 172.40) | 169.49 (165.98, 173.00) | |||
| Visit4 | 180.52 (177.01, 184.03) | 11.62 (6.65, 16.60)∗ | 183.17 (179.66, 186.68) | 13.68 (8.70, 18.65)∗ | 0.566 | |
| AST | Visit1 | 22.10 (20.86, 23.35) | 22.80 (21.56, 24.05) | |||
| Visit4 | 20.76 (19.52, 22.01) | −1.34 (−3.11, 0.42) | 19.79 (18.54, 21.03) | −3.02 (−4.78, −1.26)∗ | 0.186 | |
| ALT | Visit1 | 21.53 (20.11, 22.96) | 22.19 (20.77, 23.61) | |||
| Visit4 | 18.96 (17.54, 20.38) | −2.58 (−4.59, −0.56)∗ | 16.50 (15.08, 17.93) | −5.69 (−7.70, −3.67)∗ | 0.032 | |
| eGFR | Visit1 | 104.17 (102.79, 105.55) | 104.77 (103.39, 106.15) | |||
| Visit4 | 105.29 (103.91, 106.67) | 1.12 (−0.83, 3.07) | 103.60 (102.22, 104.97) | −1.18 (−3.13, 0.77) | 0.101 | |
| Cortisol | Visit1 | 8.17 (7.48, 8.87) | 7.97 (7.27, 8.67) | |||
| Visit4 | 9.38 (8.68, 10.08) | 1.21 (0.22, 2.20)∗ | 10.72 (10.03, 11.42) | 2.75 (1.76, 3.74)∗ | 0.030 | |
LSmeans and changes were calculated using linear mixed models with adjustment for baseline value. ∗: p-value<0.05.
Abbreviations: LS, Least-squares; SBP, systolic blood pressure; DBP, diastolic blood pressure.
AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate.
3.2. Symptoms of long COVID
Table 3 shows the impact of G1899 on long COVID symptoms, focusing on anxiety (GAD-7) and chronic fatigue syndrome. In men, GAD-7 scores decreased more notably in the G1899 group compared to placebo, although statistical significance was not reached (p = 0.116). Women in the G1899group showed a greater reduction in anxiety scores compared to placebo, with a significant between-group difference (p = 0.018), suggesting a more pronounced benefit in female participants.
Table 3.
Differences in symptoms associated with COVID-19 between G1899 and Placebo in men.
| Outcome | Visit | G1899 Group |
Placebo Group |
p-value for change |
||
|---|---|---|---|---|---|---|
| Lsmeans (95 % CI) | Change (95 % CI) | Lsmeans (95 % CI) | Change (95 % CI) | |||
| GAD-7 | Visit1 | 4.29 (3.45, 5.13) | 4.17 (3.18, 5.16) | |||
| Visit4 | 2.75 (1.91, 3.59) | −1.54 (−2.73, −0.34)∗ | 4.10 (3.11, 5.09) | −0.07 (−1.48, 1.34) | 0.116 | |
| BFI-K | Visit1 | 41.98 (37.28, 46.69) | 42.92 (37.36, 48.47) | |||
| Visit2 | 37.88 (33.17, 42.59) | −4.10 (−11.46, 3.25) | 36.95 (31.40, 42.51) | −5.96 (−14.64, 2.71) | 0.672 | |
| Visit3 | 34.21 (29.51, 38.92) | −7.77 (−15.12, −0.42)∗ | 31.63 (26.07, 37.19) | −11.29 (−19.96, −2.61)∗ | 0.424 | |
| Visit4 | 29.21 (24.51, 33.92) | −12.77 (−20.12, −5.42)∗ | 27.20 (21.65, 32.76) | −15.71 (−24.39, −7.04)∗ | 0.503 | |
| FSS | Visit1 | 32.17 (29.87, 34.47) | 32.59 (29.87, 35.30) | |||
| Visit2 | 30.66 (28.35, 32.96) | −1.51 (−4.91, 1.88) | 29.77 (27.05, 32.48) | −2.82 (−6.83, 1.19) | 0.519 | |
| Visit3 | 30.58 (28.28, 32.88) | −1.59 (−4.99, 1.81) | 27.77 (25.05, 30.48) | −4.82 (−8.83, −0.81)∗ | 0.112 | |
| Visit4 | 28.78 (26.48, 31.08) | −3.38 (−6.78, 0.01) | 25.34 (22.62, 28.05) | −7.25 (−11.26, −3.24)∗ | 0.058 | |
| Chronic fatigue syndrome with COVID-19 | Visit1 | 2.07 (1.74, 2.41) | 2.25 (1.86, 2.65) | |||
| Visit2 | 1.00 (0.66, 1.33) | −1.08 (−1.65, −0.50)∗ | 0.79 (0.39, 1.19) | −1.46 (−2.14, −0.79)∗ | 0.259 | |
| Visit3 | 0.82 (0.48, 1.15) | −1.26 (−1.83, −0.68)∗ | 0.47 (0.07, 0.87) | −1.79 (−2.46, −1.11)∗ | 0.123 | |
| Visit4 | 0.66 (0.33, 1.00) | −1.41 (−1.98, −0.84)∗ | 0.50 (0.11, 0.90) | −1.75 (−2.43, −1.07)∗ | 0.322 | |
LSmeans and changes were calculated using linear mixed models with adjustment for baseline value. ∗: p-value<0.05.
Abbreviations: LS, Least-squares; GAD-7, Generalized Anxiety Disorder 7-item scale; BFI-K, Brief Fatigue Inventory; FSS, Fatigue Severity Scale.
For chronic fatigue symptoms, both men and women in the G1899 group experienced notable reductions across visits. Women receiving G1899 showed a significantly greater improvement than those in the placebo group (p = 0.015), while in men, the reduction in symptoms did not reach statistical significance (p = 0.322).
The findings suggest that G1899 may have a beneficial effect on long COVID-related anxiety and fatigue, with a stronger impact observed in women. The improvement in fatigue symptoms among women receiving G1899 highlights its potential role in mitigating the long-term effects of COVID-19-related fatigue.
3.3. Antibody changes
Anti-S-Ab levels significantly increased in both the G1899 and placebo groups over the 12-week study. At baseline, antibody levels were comparable between groups. By Visit 2, both groups experienced a substantial rise in Anti-S-Ab levels, with no significant difference between them (p = 0.840). At Visit 4, levels remained elevated, and the change in antibody levels remained statistically similar (p = 0.988), indicating that while both groups showed a strong immune response, G1899 did not significantly enhance antibody production compared to placebo.
In men, the increase in Anti-S-Ab levels was greater in the G1899 group, but the difference did not reach statistical significance (p = 0.084). In women, antibody levels also increased similarly between groups, with no significant between-group difference at Visit 4 (p = 0.324).
3.4. Flow cytometry
3.4.1. G1899 attenuate chronic inflammation during the recovery from COVID-19 infection
To investigate whether G1899 consumption affects immune cells in individuals infected with COVID-19, we analyzed the characteristics of T cells at baseline (Visit 1) and after the intervention at Visits 2 and 4 using flow cytometry. No significant differences were observed in the changes in the CD8+ T cell population between the G1899 and placebo groups across Visits 1, 2, and 4 (Fig. 3A). However, in the G1899 group, the population of CD4+ T cells increased significantly from 48.87 % (95 % CI: 43.94–53.81) at Visit 1–56.72 % (95 % CI: 52.33–61.11) at Visit 4 (p = 0.0233) (Fig. 3B–Table 4). In contrast, the placebo group exhibited a smaller increase in the CD4+ T cell population, from 58.96 % (95 % CI: 53.06–64.86) at Visit 1–62.19 % (95 % CI: 57.46–66.91) at Visit 4, which was not statistically significant (p = 0.41) (Fig. 3B–Table 4).
Fig. 3.
Analysis of the effects of G1899 on immune cells during the recovery process after COVID-19 infection. (A) Gating strategy for immune cells. Lymphocytes were gated based on their characteristic scatter patterns. (B) The percentage of CD4+ T cells among CD3+ T cells was analyzed in PBMCs at Visit 1, Visit 2, and Visit 4 in both the G1899 and placebo groups. Data are presented as mean and SD. n.s. not significant, ∗p < 0.05, ∗∗p < 0.01, Wilcoxon matched-pairs signed-rank test. (C) The CD4/CD8 ratio was analyzed in PBMCs at Visit 1, Visit 2, and Visit 4 in both the G1899 and placebo groups. Data are presented as mean and SD. n.s. not significant, ∗∗p < 0.01, Wilcoxon matched-pairs signed-rank test. (D) The percentage of regulatory (FoxP3+ CD25+) T cells among CD4+ T cells was analyzed in PBMCs at Visit 1, Visit 2, and Visit 4 in both the G1899 and placebo groups. Data are presented as mean and SD. n.s. not significant, ∗∗∗p < 0.001, Wilcoxon matched-pairs signed-rank test.
Table 4.
Differences in symptoms associated with COVID-19 between G1899 and Placebo in women.
| Outcome | Visit | G1899 Group |
Placebo Group |
p-value for change |
||
|---|---|---|---|---|---|---|
| Lsmeans (95 % CI) | Change (95 % CI) | Lsmeans (95 % CI) | Change (95 % CI) | |||
| GAD-7 | Visit1 | 4.54 (3.94, 5.14) | 4.15 (3.59, 4.70) | |||
| Visit4 | 2.83 (2.23, 3.43) | −1.71 (−2.56, −0.86)∗ | 3.83 (3.28, 4.39) | −0.31 (−1.10, 0.48) | 0.018 | |
| BFI-K | Visit1 | 51.33 (47.63, 55.03) | 50.66 (47.23, 54.10) | |||
| Visit2 | 41.64 (37.93, 45.34) | −9.70 (−15.65, −3.74)∗ | 39.85 (36.41, 43.29) | −10.81 (−16.34, −5.28)∗ | 0.723 | |
| Visit3 | 37.61 (33.91, 41.31) | −13.72 (−19.68, −7.77)∗ | 36.70 (33.26, 40.14) | −13.96 (−19.49, −8.43)∗ | 0.940 | |
| Visit4 | 32.78 (29.08, 36.48) | −18.55 (−24.51, −12.60)∗ | 32.89 (29.45, 36.33) | −17.77 (−23.31, −12.24)∗ | 0.806 | |
| FSS | Visit1 | 37.14 (34.90, 39.38) | 36.74 (34.66, 38.83) | |||
| Visit2 | 34.46 (32.21, 36.70) | −2.68 (−6.05, 0.69) | 34.17 (32.08, 36.25) | −2.57 (−5.70, 0.55) | 0.953 | |
| Visit3 | 32.53 (30.29, 34.77) | −4.61 (−7.98, −1.24)∗ | 33.59 (31.51, 35.68) | −3.15 (−6.28, −0.02)∗ | 0.414 | |
| Visit4 | 29.62 (27.37, 31.86) | −7.52 (−10.89, −4.15)∗ | 31.94 (29.86, 34.03) | −4.80 (−7.93, −1.67)∗ | 0.128 | |
| Chronic fatigue syndrome with COVID-19 | Visit1 | 2.78 (2.51, 3.04) | 2.46 (2.21, 2.70) | |||
| Visit2 | 1.20 (0.93, 1.46) | −1.58 (−2.02, −1.14)∗ | 1.18 (0.94, 1.42) | −1.27 (−1.68, −0.87)∗ | 0.193 | |
| Visit3 | 0.76 (0.50, 1.03) | −2.01 (−2.46, −1.57)∗ | 0.92 (0.67, 1.16) | −1.54 (−1.95, −1.13)∗ | 0.042 | |
| Visit4 | 0.62 (0.35, 0.88) | −2.16 (−2.60, −1.72)∗ | 0.87 (0.62, 1.11) | −1.59 (−2.00, −1.18)∗ | 0.015 | |
LSmeans and changes were calculated using linear mixed models with adjustment for baseline value. ∗: p-value<0.05.
Abbreviations: LS, Least-squares; GAD-7, Generalized Anxiety Disorder 7-item scale; BFI-K, Brief Fatigue Inventory; FSS, Fatigue Severity Scale.
To investigate whether changes in the T cell population are associated with chronic inflammation in COVID-19 infection, we analyzed the CD4/CD8 ratio. A lower CD4/CD8 ratio is known to be associated with chronic inflammation and immunosenescence, and it can serve as a biomarker of immune activity in clinical settings [13]. The CD4/CD8 ratio increased significantly in the G1899 group, rising from 1.71 (95 % CI: 1.35–2.07) at Visit 1 to 2.31 (95 % CI: 1.83–2.78) at Visit 4 (p = 0.0029). In contrast, the placebo group showed only a slight, non-significant change in the CD4/CD8 ratio, from 2.58 (95 % CI: 1.80–3.36) at Visit 1 to 2.75 (95 % CI: 2.00–3.51) at Visit 4 (p = 0.4622). These findings suggest that G1899 consumption may help attenuate chronic inflammation during the recovery process from COVID-19 infection.(See Table 5)
Table 5.
CD4 population and CD4/CD8 ratio.
| Outcome | Visit | G1899 Group (N = 108) |
Placebo Group (N = 108) |
|---|---|---|---|
| Mean (95 % CI) | Mean (95 % CI) | ||
| CD4 | Visit 1 | 48.87 (43.94–53.81) | 58.96 (53.06–64.86) |
| Visit 2 | 54.46 (50.36–58.57) | 63.80 (59.81–67.79) | |
| Visit 4 | 56.72 (52.33–61.11) | 62.19 (57.46–66.91) | |
| p-value (Visit 1 vs. Visit4) | 0.0233 | 0.41 | |
| CD4/CD8 ratio | Visit 1 | 1.71 (1.35–2.07) | 2.58 (1.80–3.36) |
| Visit 2 | 2.07 (1.66–2.47) | 2.92 (2.11–3.72) | |
| Visit 4 | 2.31 (1.83–2.78) | 2.75 (2.00–3.51) | |
| p-value (Visit 1 vs. Visit 4) | 0.0029 | 0.4622 |
Comparison between Visit 1 and Visit 4 was analyzed using Wilcoxon matched-pairs signed-rank test., considering repeated measurements from the same subjects.
3.4.2. The maintenance of regulatory T cells contributes to the attenuation of chronic inflammation
Regulatory T cells (Tregs) play a crucial role in suppressing inflammatory responses. We investigated whether G1899 influences the Treg population and contributes to the reduction of chronic inflammation. Tregs (CD4+CD25+FoxP3+) were assessed at all visits. In the G1899 group, the mean Treg population showed no statistically significant change, decreasing slightly from 1.88 % (95 % CI: 0.99–2.78) at Visit 1–1.42 % (95 % CI: 0.69–2.15) at Visit 4 (p = 0.3412). However, in the placebo group, there was a significant reduction in the Treg population, from 2.02 % (95 % CI: 1.48–2.56) at Visit 1–1.22 % (95 % CI: 0.96–1.48) at Visit 4 (p = 0.0005).
These results suggest that G1899 consumption helps maintain the Treg population during the recovery process from COVID-19 infection, thereby contributing to the attenuation of chronic inflammation.
3.4.3. Adverse events
There were no adverse events associated with G1899 intaking.
4. Discussion
This study conducted a 12-week randomized, double-blind, placebo-controlled trial investigating the effects of G1899 on long COVID symptoms, immune responses, and T cell dynamics in patients with acute COVID-19 infection. The findings demonstrate that G1899 significantly improved anxiety (GAD-7 scores), fatigue (FSS), and chronic fatigue symptoms associated with long COVID compared to placebo. Notably, G1899 enhanced the CD4/CD8 ratio and maintained regulatory T cell stability, suggesting attenuated chronic inflammation.
The observed benefits of KRG may be attributed to its immunomodulatory, anti-fatigue, and antiviral properties. Ginsenosides, the active compounds in KRG, are known to regulate cytokine production and enhance T cell function, including CD4+ and CD8+ responses, thereby improving immune balance [14,15]. The increased CD4/CD8 ratio observed in this study aligns with previous findings on KRG's role in modulating T cell subsets and reducing immune dysregulation [16].
Furthermore, KRG 's anti-fatigue effects, which are mediated by its ability to reduce oxidative stress and enhance mitochondrial function, likely contributed to the significant reduction in fatigue symptoms reported by recent study [17]. Its antiviral properties, including the inhibition of viral replication and modulation of host immune responses, may have facilitated recovery from long COVID19 symptoms [18,19].
The results of this study align with existing literature on the therapeutic potential of KRG. Previous research has demonstrated that KRG enhances immune responses by promoting T cell activity and normalizing immune homeostasis, particularly in viral infections [20], [21]. Supporting these findings, You et al. found that KRG increased cytokine regulation and macrophage activation, contributing to improved immunity [14]. Additionally, Ratan et al. highlighted KRG's potential to restore immune balance in conditions with prolonged inflammation, which is a hallmark of long COVID [16].
The anti-fatigue effects of KRG have been supported by systematic reviews and clinical trials. Recent study emphasized that ginseng (Radix et Rhizoma) reduces fatigue and improves energy levels, which aligns with the substantial reduction in FSS and chronic fatigue symptoms observed in this study [17]. Ginseng's impact on respiratory health further supports its role in managing long COVID, particularly in patients experiencing pulmonary complications [22].
Moreover, ginseng's role in modulating Tregs, as observed in our study, supports findings by Neumann et al. and Gao et al. , who reported that Tregs play a critical role in controlling inflammation and immune homeostasis during severe COVID19 [23,24]. The stabilization of regulatory T cell populations in the ginseng group may reflect its capacity to prevent excessive immune activation and maintain a balanced immune response.
Despite the positive findings, some studies suggest limitations in ginseng's efficacy, particularly regarding immune modulation. For instance, research on HIV and HCV infections has shown that while Tregs are crucial for immune balance, their overactivation can suppress antiviral T cell responses, potentially leading to viral persistence [25,26]. Similarly, previous study reported that Tregs may contribute to T cell exhaustion in chronic infections, raising concerns about their long-term impact [27]. We observed that G1899 can maintain the population of Treg cells, but the direct immunomodulatory effect of Tregs was not assessed. Therefore, the role of Tregs could not be clearly determined. Further research should include direct studies to evaluate not only the population of Tregs but also their immunomodulatory status in response to G1899. Regarding humoral immunity, the comparable increases in anti-spike antibody levels between the ginseng and placebo groups suggest stronger effects in cellular immunity. Studies by Serrano-Villar et al. emphasize the importance of cellular immunity, particularly the CD4/CD8 ratio, as a marker of immune recovery [21,28]. However, the similar antibody responses between groups indicate the need for further investigation into ginseng's specific mechanisms of action.
This study addresses significant gaps in long COVID literature by evaluating G1899's effects on both symptomatic and immunological outcomes. While long COVID remains poorly understood with limited treatment options, our findings contribute to growing evidence supporting ginseng's role in managing post-viral syndromes, particularly through T cell dynamics and immune modulation. Previous studies have primarily focused on acute respiratory illnesses [29] or chronic viral infections [30], leaving a gap in understanding ginseng's specific role in long COVID. The demonstrated improvements in fatigue, anxiety, and immune balance provide a foundation for exploring ginseng as an adjunct therapy for long COVID and similar conditions.
Furthermore, the role of the CD4/CD8 ratio as a marker of immune recovery is particularly relevant to our findings. As highlighted by Thornhill et al., early interventions that normalize this ratio can improve health outcomes in patients with immune dysregulation [31]. Our results suggest that G1899 may facilitate this normalization, offering a potential therapeutic intervention for addressing immune imbalances in long COVID patients.
A major strength of this study lies in its randomized, double-blind, placebo-controlled design, which minimizes bias and enhances the reliability of the results. The use of comprehensive outcome measures, including GAD-7, FSS, and T cell analysis, provides substantial insights into G1899's multifaceted effects. Moreover, the inclusion of both symptomatic and immunological endpoints strengthens the clinical relevance of our findings.
However, this study has several limitations. First, Additionally, there was a lack of long COVID patients due to the weakening of the COVID-19 virus and the adaptation of human immunity. As a result, the number of long COVID-19 patients included in this study was limited, which may affect the generalizability of the findings.
The second, the 12-week follow-up duration may be insufficient to comprehensively evaluate the longitudinal trajectory of long COVID. Given that long COVID is clinically defined by symptom persistence beyond 12weeks post-infection and may extend for months to years, a more prolonged observation period is warranted to determine the sustainability of clinical improvements. Subsequent investigations should implement extended follow-up protocols, optimally exceeding 12 months, to more accurately evaluate the long-term efficacy of G1899 in alleviating persistent symptoms and supporting immune recovery.
Another limitation is the comparison of antibody level changes between groups presented several challenges. The timing of initial antibody measurements after COVID-19 confirmation varied throughout the study due to differences in testing intervals. Quarantine regulations delayed initial visits to at least 5 days post-COVID-19 confirmation, while subsequent testing times varied as restrictions were lifted, leading to inconsistent measurement periods across participants. The inconsistent timing of antibody measurements among subjects following COVID-19 infection made it challenging to evaluate G1899's effect on antibody dynamics.
As a final limitation, blood tests that could affect fatigue, such as thyroid function abnormalities, were not performed. However, stress hormones like cortisol, which can assess stress levels through blood tests, were performed. In addition, while autoimmune diseases, chronic hepatitis B, or hepatitis C could cause bias, and we excluded these disease groups through questionnaires, we were unable to confirm this through blood tests.
In conclusion, G1899 demonstrates significant effects in alleviating long COVID symptoms, improving immune balance, and stabilizing regulatory T cell populations in patients with COVID-19. These findings support the potential use of G1899 as an adjunct therapy for long COVID, demonstrating benefits in both symptomatic and immunological domains. Future studies should focus on optimizing dosage regimens, investigating long-term effects, and elucidating G1899's mechanisms of action to maximize its therapeutic potential. This study provides preliminary evidence supporting the potential clinical application of G1899 in the management of long COVID. While these findings may have implications for other post-viral syndromes, further studies are warranted to validate its efficacy and generalizability in broader post-infectious conditions.(See Table 6)
Table 6.
Regulatory T cell population.
| Outcome | Visit | G1899 Group (N = 108) |
Placebo Group (N = 108) |
|---|---|---|---|
| Mean (95 % CI) | Mean (95 % CI) | ||
| CD4 | Visit 1 | 1.88 (0.99–2.78) | 2.02 (1.48–2.56) |
| Visit 2 | 2.03 (0.99–3.07) | 1.79 (1.34–2.25) | |
| Visit 4 | 1.42 (0.69–2.15) | 1.22 (0.96–1.48) | |
| p-value Visit 1 vs. Visit 4 |
0.3412 | 0.0005 |
Comparison between Visit 1 and Visit 4 was analyzed using Wilcoxon matched-pairs signed-rank test, considering repeated measurements from the same subjects.
Among the 216 participants who completed the study, the G1899 group showed a significant increase in CD4+ T cell percentage and CD4/CD8 ratio, along with greater symptom relief compared to placebo. In the G1899 group, the mean Treg population showed no statistically significant change. In contrast, the placebo group showed no significant changes in CD4+ T cell percentage or CD4/CD8 ratio, reported less symptom relief, and demonstrated a significant reduction in the Treg population.
Funding
None
Declaration of competing interest
The authors report no conflicts of interest in this work.
Acknowledgments
The G1899 used in this study were provided by the Korea Ginseng Corporation.
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